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EP2015752B1 - Antagonistes de kinase p13 - Google Patents

Antagonistes de kinase p13 Download PDF

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Publication number
EP2015752B1
EP2015752B1 EP07873406.8A EP07873406A EP2015752B1 EP 2015752 B1 EP2015752 B1 EP 2015752B1 EP 07873406 A EP07873406 A EP 07873406A EP 2015752 B1 EP2015752 B1 EP 2015752B1
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unsubstituted
substituted
alkyl
cycloalkyl
heterocycloalkyl
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German (de)
English (en)
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EP2015752A4 (fr
EP2015752A2 (fr
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Zachary A. Knight
Kevan M. Shokat
Olusegun Williams
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University of California
University of California Berkeley
University of California San Diego UCSD
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University of California
University of California Berkeley
University of California San Diego UCSD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Phosphoinositide 3-kinases catalyze the synthesis of the phosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P2, and PI(3,4,5)P3 (PIP3) (Fruman et al., 1998).
  • PI phosphatidylinositol
  • PI(3,4)P2 phosphatidylinositol
  • PIP3 PI3-Ks
  • these three lipids control diverse physiological processes including cell growth, survival, differentiation and chemotaxis.
  • the PI3-K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001).
  • the class I PI3-Ks (p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ ) are activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as the Akt/PDK1 pathway, the Tec family kinases, and the Rho family GTPases.
  • the class II and III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.
  • the PIKKs are protein kinases that control cell growth (mTORC1) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).
  • the present invention meets these and other needs in the art by providing a new class of PI3-Kinase antagonists.
  • the present invention provides certain novel compounds found to be effective as antagonists of PI3-Kinases.
  • the present invention provides a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist) or a PI3-kinase antagonist as set forth in the clams.
  • a PI3-Kinase affinity pocket binding antagonist e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • a PI3-kinase antagonist as set forth in the clams.
  • the method includes the step of contacting the PI3-Kinase with an activity decreasing amount of a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist) or a PI3-Kinase antagonist of Formula (I).
  • a PI3-Kinase affinity pocket binding antagonist e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • PI3-Kinase antagonist of Formula (I) e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • the method includes administering to the subject a therapeutically effective amount of a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist) or a PI3-Kinase antagonist of Formula (I).
  • a PI3-Kinase affinity pocket binding antagonist e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • PI3-Kinase antagonist of Formula (I) e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • the method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist) or a PI3-Kinase antagonist of Formula (I).
  • a PI3-Kinase affinity pocket binding antagonist e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • PI3-Kinase antagonist of Formula (I) e.g. a PI3-Kinase affinity pocket quinazolinone antagonist
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated ( i . e. C 1 -C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CHCHCH 2 -, -CH 2 C ⁇ CCH 2 -, -CH 2 CH 2 CH(CH 2 CH 2 CH 3 )CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • An “alkynylene” is a subset of an alkylene in which the alkylene includes at least on triple bond between adjacent carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 ,-S(O)-CH 3 .
  • Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini ( e.g ., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", - OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • cycloalkylene and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Nonlimiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinoly
  • arylene and heteroarylene refer to the divalent radicals of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e . g ., aryloxo, arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group ( e . g ., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom ( e . g ., a methylene group) has been replaced by, for example, an oxygen atom ( e .
  • haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
  • heteroalkyl where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members ( e . g . "3 to 7 membered"), the term “member” referrers to a carbon or heteroatom.
  • oxo as used herein means an oxygen that is double bonded to a carbon atom.
  • R', R", R'" and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen radical.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • acyl e . g ., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C"R'") d -, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or "ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • aminoalkyl refers to an amino group covalently bound to an alkylene linker.
  • the amino group is -NR'R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a “substituent group,” as used herein, means a group selected from the following moieties:
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyi.
  • a “lower substituent” or “ lower substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • the compounds of the present invention may exist as salts.
  • the present invention includes such salts.
  • Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in art.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19 ).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • a when used in reference to a group of substituents herein, mean at least one.
  • a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R substituent the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer.
  • an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease.
  • An “effective amount may also be referred to as a "therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) a disease, or reducing the likelihood of the onset (or reoccurrence) of a disease or its symptoms.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzymne relateive to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an ostcociast or leukocyte relative to the absence of the antagonist.
  • the "antagonist” or “the compound as described herein” refers to a compound of Formula (I), or a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist).
  • a "compound of Formula (I)” includes all embodiments of Formula (I) as described below.
  • the PI3-kinase antagonist is a PI3-Kinase affinity pocket binding antagonist (e.g. a PI3-Kinase affinity pocket quinazolinone antagonist).
  • the PI3-Kinase affinity pocket binding antagonist described herien is a compound containing a PI3-Kinase affinity pocket binding moiety.
  • the PI3-Kinase affinity pocket quinazolinone antagonists described herein are substituted quinazolinone compounds containing a PI3-Kinase affinity pocket binding moiety.
  • the PI3-Kinase affinity pocket binding moiety is a substituent which, upon contacting a p110 ⁇ , p110 ⁇ , p110 ⁇ , or p110 ⁇ kinase, fills space within the corresponding PI3-Kinase affinity pocket.
  • the PI3-Kinase affinity pocket binding moiety may displace at least one water molecule within the PI3-Kinase affinity pocket.
  • the PI3-Kinase affinity pocket binding moiety may also interact with one or more amino acids that from part of the PI3-Kinase affinity pocket.
  • a description of the PI3-Kinase affinity pocket and methods of determining whether a substituent fills space within the PI3-Kinase affinity pocket are set forth below.
  • the PI3-Kinase affinity pocket quinazolinone antagonist may further include a pyraxolopyrimidine substituent or a pyrrolopyrimidine substituent.
  • the pyrazolopyrimidine substituent or pyrrolopyrimidine substituent is covalently bonded to the quinazolinone core, and the PI3-Kinase affinity pocket binding moiety is covalentty attached to the pyrazolopyrimidine substituent or pyrrolopyrimidine substituent.
  • the P13-kinase antagonist described herein has the formula:
  • L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 1 and R 2 are independently halogen, -CN, -OR 5 , -S(O) n R 6 , -NR 7 R 8 , -C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, where n is an integer from 0 to 2.
  • R 1 may also be a PI3-Kinase affinity pocket binding moiety.
  • R 3 and R 4 are independently hydrogen, halogen, -CN, -OR 5 , -S(O) n R 6 , -NR 7 R 8 , -C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, where n is an integer from 0 to 2.
  • R 5 is independently hydrogen, -C(O)R 10 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is independently hydrogen, -NR 11 R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Where n is 1 or 2, R 6 is other than hydrogen.
  • R 7 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 8 is independently hydrogen, -S(O) n R 13 , -C(O)R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 9 is independently -NR 15 R 16 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 10 is independently hydrogen, -NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 14 is independently hydrogen, -NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
  • R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the PI3-Kinase affinity pocket binding moiety is capable of forming a hydrogen bond with the side chain amine of K833, an amino acid within the PI3-Kinase affinity pocket.
  • R 1 is halogen, substituted or unsubstituted halo(C 1 -C 6 )alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl(C 1 -C 6 )alkyl, or substituted or unsubstituted heteroaryl(C 1 -C 6 )alkyl.
  • R 1 may also be halogen, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiophenyl, or substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted 1H-pyrrolo[2,3-c]pyridinyl, substituted or unsubstituted 1H-pyrrolo[2,3-b]pyridinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstit
  • R 1 is phenyl, furanyl, pyrrolyl, thiophenyl, or benzothiophenyl, each of which are optionally substituted with one or more R 21 substituent(s).
  • R 21 is independently (1) or (2) as defined in this paragraph.
  • R 21 may be (1) halogen, -CN, -OR 22 , -C(O)R 23 , -NR 2 °R 25 , -S(O) w NR 26 R 27 , or -S(O) w R 28 .
  • R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, or heteroarylalkyl, optionally substituted with unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl.
  • R 21 may also be (2) (C 1 -C 10 )alkyl, 2 to 10 membered heteroalkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocycloalkyl, aryl or heteroaryl optionally substituted with halogen, -OH, -CN, -NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl.
  • R 1 is phenyl substituted at the meta and para positions, or substituted at the meta and meta positions. That is, R 1 is a 4,5-substituted phenyl or a 3,5-substituted phenyl. In some related examples, the 4,5-substituted phenyl or 3,5-substituted phenyl is substituted, independently, with R 21 (as defined in the previous paragraph). In some examples, R 21 is halogen or -OR 22 . R 21 may also be fluorine and R 22 may be hydrogen or unsubstituted C 1 -C 4 alkyl (e.g. methyl). In other examples, R is phenyl substituted para position (i.e. a 4-substituted phenyl).
  • L 1 is substituted or unsubstituted alkylene (e.g. a substituted or unsubstituted alkynylene.
  • L 1 is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylenes, substituted or unsubstituted ethynylene, or substituted or unsubstituted prop-2-ynylene.
  • R 1 is -CN, -OR 5 , NR 7 R 8 , R 21 -substituted or unsubstituted cycloalkyl, R 21 -substituted or unsubstituted aryl, R 21 -substituted or unsubstituted heteroaryl, R 21 -substituted or unsubstituted C 1 -C 4 alkyl.
  • R 21 may be halogen, -OR 22 , -NR 24 R 25 , or unsubstituted C 1 -C 4 alkyl.
  • R 5 , R 7 , R 8 , R 22 , R 24 and R 25 may independently be hydrogen or unsubstituted C 1 -C 4 alkyl (e.g. methyl).
  • R 2 is halogen, -OH, -CN, -NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl.
  • R 2 may also be halogen or unsubstituted alkyl.
  • R is fluorine or unsubstituted C 1 -C 4 alkyl (e.g. methyl).
  • R 3 may be halogen, -OH, -CN, -NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cyeloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylatkyl.
  • R 3 may also be unsubstituted C 1 -C 4 alkyl (e.g. methyl).
  • R 4 is halogen, -OH, -CN, -NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarytalkyl.
  • R 2 and R 3 are independently unsubstituted C 1 -C 4 alkyl, R 4 is NH 2 , q is 1, and z is 1.
  • each substituted group described above in the compound of Formula (I) is substituted with at least one substituent group. More specifically, in some examples each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl-alkyl, substituted heterocycloalkyl-alkyl, substituted arylalkyl, and/or substituted heteroarylalkyl, described above in the compounds of Formula (I) is substituted with at least one substituent group. In other cases, at least one or all of these groups are substituted with at least one size-limited substituent group. Alternatively, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, including those alkyl groups forming part of a cycloalkyl-alkyl (i.e. a cycloalkyl-(C 1 -C 20 )alkyl), heterocycloalkyl-alkyl (i.e. a heterocycloalkyl-(C 1 -C 20 )alkyl), arylalkyl (i.e. an aryl-(C 1 -C 20 )alkyl), or substituted heteroarylalkyl (i.e. a heteroaryl-(C 1 -C 20 )alkyl).
  • a cycloalkyl-alkyl i.e. a cycloalkyl-(C 1 -C 20 )alkyl
  • heterocycloalkyl-alkyl i.e. a heterocycloalkyl-(C 1 -
  • Each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl.
  • Each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, including those cycloalkyl groups forming part of a cycloalkyl-alkyl (i.e. a C 4 -C 8 cycloalkyl-alkyl, or a C 4 -C 8 cycloalkyl-(C 1 -C 20 )alkyl).
  • Each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl, including those heterocycloalkyl groups forming part of a heterocycloalkyl-alkyl (i.e. a 4 to 8 membered heterocycloalkyl-alkyl, or a 4 to 8 membered heterocycloalkyl-(C 1 -C 20 )alkyl).
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl, including cycloalkyl-alkyl groups, heterocycloalkyl-alkyl groups, heteroarylalkyl groups, and arylalkyl groups, as described in the preceding paragraph.
  • the compounds of the present invention include the compounds of any one or all of those listed in Table 1 below.
  • PI3-Kinase affinity pocket refers to a cavity within p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ corresponding to the lightly shaded region shown in Figures 2A, 2C, and 2D labeled "Affinity Pocket.”
  • Figures 2A, 2C, and 2D illustrate a computer model of the p110 ⁇ crystal structure.
  • the surface of the PI3-Kinase affinity pocket is bound, at least in part, by the side chain of K833, D964, I879, and D841 (p110 ⁇ numbering, see Figure 8 ).
  • the surface of the corresponding cavity in p110 ⁇ is bound, at least in part, by the side chain of K779, D911, I825, and D787 (p110 ⁇ numbering, see Figure 7 ).
  • the corresponding cavity within p110 ⁇ is bound, at least in part, by the side chains of K802, D933, I848, and D810 (p110 ⁇ numbering, see Figure 9 ).
  • the corresponding cavity within p110 ⁇ is bound, at least in part, by the side chains of K805, D937, I851, and D813 (p110 ⁇ numbering, see Figure 10 ).
  • the PI3-Kinase affinity pocket is not accessed by ATP.
  • the PI3-Kinase affinity pocket of p110 ⁇ may be referred to herein as the p110 ⁇ affinity pocket.
  • the PI3-Kinase affinity pocket of p110 ⁇ may be referred to herein as the p110 ⁇ affinity pocket.
  • the PI3-Kinase affinity pocket includes lysine 779, which, according to computer models, forms a hydrogen bond with the pyridine nitrogen of PIK-90 and the phenol oxygen of PI 103 ( Figure 2D ), both of which are inhibitors of p110 ⁇ . Based on these computer modeling results, a novel antagonist was designed based on the chemical structure of PIK-39 and IC87114, as detailed below.
  • PIK-39 does not contain a PI3-Kinase binding pocket moiety.
  • IC87114 maintains contacts to E880 and V882 in the ATP binding region of p110 ⁇ , but is also missing a PI3-Kinase binding pocket moiety.
  • m -phenol a PI3-Kinase binding pocket moiety
  • the PI3-Kinase affinity pocket is accessed ( FIG. 3A ) resulting in a 60-fold increase in p110 ⁇ inhibition potency.
  • a PI3-Kinase binding pocket moiety is a substituent which, upon contacting upon contacting p110 ⁇ , p110 ⁇ , p110 ⁇ , or p110 ⁇ , fills space within the corresponding PI3-Kinase binding pocket.
  • a PI3-Kinase affinity pocket binding moiety is a substituent which, upon contacting upon contacting p110 ⁇ , fills space within the p110 ⁇ affinity pocket.
  • a p110 ⁇ affinity pocket binding moiety is a substituent which, upon contacting upon contacting p110 ⁇ , fills space within the p110 ⁇ affinity pocket.
  • the antagonist interact with or displaces the side chain of methionine 804 of p110 ⁇ , or the equivalent methionine present in p110 ⁇ , p110 ⁇ , or p110 ⁇ (See Figures 7-10 ).
  • the PI3-Kinase binding pocket moiety may additionally interact (e.g. bonds) with an amino acid that forms part of the PI3-Kinase binding pocket.
  • the interaction is a hydrogen bond, van der Waals interaction, ionic bond, covalent bond (e.g. disulfide bond) or hydrophobic interaction.
  • a query PI3-Kinase affinity pocket binding antagonist i.e. a test compound
  • the p110 ⁇ computer image is derived from the solved co-crystal structure of human p110 ⁇ bound to PIK-39.
  • the PyMOL Molecular Graphics System may be employed to generate the image.
  • An example is presented in Figure 3A , wherein IC87114 and PIK-294 are built into the computer image of p110 ⁇ kinase, derived from the p110 ⁇ - PIK-39 co-crystal. See Knight, et al., Cell 125: 733-745 (2006 ).
  • the computer models are typically analyzed to prevent any gross steric clashes and to satisfy key hydrogen bonds between the query PI3-Kinase affinity pocket binding antagonist and the p110 ⁇ protein (e.g. V882 and M804). In some cases, energy minimization calculations are performed to optimize binding energy. Using these techniques, one skilled in the art can easily determine whether a query PI3-Kinase affinity pocket binding antagonist includes a PI3-Kinase affinity pocket binding moiety that fills space within the PI3-Kinase affinity pocket.
  • the query PI3-Kinase affinity pocket binding antagonist is analyzed to determine whether at least one bond (e.g. a hydrogen bond) is formed between the query PI3-Kinase affinity pocket binding antagonist and an amino acid that form part of the PI3-Kinase affinity pocket.
  • at least one bond e.g. a hydrogen bond
  • the distance between one or more amino acids that form part of the PI3-Kinase affinity pocket and a potential contact point on the PI3-Kinase affinity pocket binding moiety is determined. Based on this distance, one skilled in the art may determine whether at least one bond is formed between one or more amino acids that form part of the PI3-Kinase affinity pocket and a PI3-Kinase affinity pocket binding moiety.
  • the compounds described herein are synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds described herein. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds.
  • R 1 , R 2 , R 3 , X, and q are as defined above.
  • the anthranilic acid E1 may be converted to the acid chloride using, for example, SOCl 2 and then directly reacted with the amino functionality of an aniline to yield the corresponding amide E2.
  • E2 may be accomplished using chloroacetylchloride.
  • substitution of the E3 chlorine with the iodo-pyrazolopyrimidine or iodo-pyrrolopyrimidine is performed in the presence of base to form E4 .
  • the iodine of E4 is substituted with R 1 by a Suzuki-Miyaura coupling with the appropriate boronic acid.
  • a PI3 kinase such as p110 ⁇ kinase or p110 ⁇ kinase.
  • the method includes the step of contacting the PI3 kinase (e.g. p110 ⁇ , kinase) with an activity decreasing amount of a PI3-Kinase antagonist (i.e. a PI3-Kinase affinity pocket binding antagonist or a PI3-Kinase antagonist of Formula (I)).
  • the antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist.
  • the PI3-Kinase antagonist is specific to p110 ⁇ relative to the antagonist action against p110 ⁇ , p110 ⁇ , and/or p110 ⁇ . In some examples, the PI3-Kinase antagonist is specific to p110 ⁇ relative to the antagonist action against p110 ⁇ and/or p110 ⁇ . In some examples, the PI3-Kinase antagonist is specific to p110 ⁇ relative to the antagonist action against p110 ⁇ . In some examples, the PI3-Kinase antagonist is specific to p110 ⁇ relative to the antagonist action against p110 ⁇ and/or p110 ⁇ . In some examples, the PI3-Kinase antagonist is specific to p110 ⁇ relative to the antagonist action against p110 ⁇ .
  • the PI3-Kinase antagonist is the PI3-Kinase antagonist of Formula (I) where R 1 is a 4,5-substituted phenyl.
  • R 1 is a 4,5-substituted phenyl.
  • the 4,5-substituted phenyl is substituted, independently, with R 21 .
  • R 21 may be halogen or -OR 22 .
  • R 21 may also be fluorine and R 22 maybe hydrogen or unsubstituted C 1 -C 4 alkyl (e.g. methyl).
  • the PI3-Kinase antagonist is the PI3-Kinase antagonist of Formula (I), where R 1 is a 3,5-substituted phenyl.
  • R 1 is a 3,5-substituted phenyl.
  • the 3,5-substituted phenyl is substituted, independently, with R 21 .
  • R 21 may be halogen or -OR 22 .
  • R 21 may also be fluorine and R 22 may be hydrogen or unsubstituted C 1 -C 4 alkyl (e.g. methyl).
  • the IC50 against the p110 ⁇ kinase and/or p110 ⁇ is at least 1.5, 2.0, 3.0, 4.0, 5.0, 10, 20, 30, 40, S0, 60, 70, 80, 90, 100, 200, 500, or 100 fold lower than the IC50 against p110a, and/or p110 ⁇ .
  • the IC50 of the antagonist against p1108 kinase and/or p110 ⁇ is less than 100 ⁇ M, 56 ⁇ M, 40 ⁇ M, 30 ⁇ M, 20 ⁇ M, 10 ⁇ M, 5 ⁇ M, 1 ⁇ M, 0.5 ⁇ M, 0.1 ⁇ M, 50 nM, 10 nM, 1 nM. 0.5 nM, 0.1 nM, 50 pM, 10 pM, or 1 pM.
  • the method includes administering to the subject a therapeutically effective amount of a PI3-Kinase antagonist (i.e. a PI3-Kinase affinity pocket antagonist or PI3-Kinase antagonist of Formula (I)).
  • the antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist.
  • the disease is a hematologic malignancy, inflammation, autoimmune disease, or cardiovascular disease.
  • the disease is a hematologic malignancy or autoimmune disease.
  • hematologic malignancies include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS).
  • hematologic malignancies include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS).
  • inflammation disorders and autoimmune disease include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and asthma.
  • Other disorders include bone-resorption disorders and thromobs
  • the disorder may also be a type of cancer or cancer metastasis, including, for example, leukemia, carcinomas and sarcomas, such as cancer of the brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and medulloblastoma.
  • leukemia carcinomas and sarcomas
  • carcinomas and sarcomas such as cancer of the brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and medulloblastoma.
  • Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine and exocrine pancreas, and prostate cancer.
  • a detailed description of conditions and disorders mediated by p110 ⁇ kinase activity is set forth in Sadu et al., WO 01/81346 .
  • the method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a PI3-Kinase antagonist (i.e., a PI3-Kinase affinity pocket antagonist or PI3-Kinase antagonist of Formula (I)).
  • a PI3-Kinase antagonist i.e., a PI3-Kinase affinity pocket antagonist or PI3-Kinase antagonist of Formula (I)
  • the antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist.
  • the present invention provides a pharmaceutical composition including a PI3-Kinase affinity pocket binding antagonist or a compound of Formula (I) in admixture with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition including a PI3-Kinase affinity pocket binding antagonist or a compound of Formula (I) in admixture with a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions include the pharmaceutically acceptable salts of the PI3-Kinase antagonists of the present invention described above.
  • the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000 ).
  • the compounds according to the invention are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • a most preferable dosage is 10 to 30 mg per day.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, steacetate
  • compositions may be found in, for example, Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000 ).
  • Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained- low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000 ).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the invention may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present invention in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g. patient) to be treated.
  • the agents of the invention may also be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer.
  • chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
  • agents the inhibitors of this invention may also be combined with include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyr
  • these additional agents may be administered separately, as part of a multiple dosage regimen, from the inhibitor-containing composition.
  • these agents maybe part of a single dosage form, mixed together with the inhibitor in a single composition.
  • PI3-Kinase agonists described above are equally applicable to the methods of treatment and methods of inhibiting kinases described herein. References cited throughout this application are examples of the level of skill in the art.
  • Scheme 2 illustrates synthetic routes to certain compounds listed in Table 1 below. Using the information provided in Schemes 1 and 2, and the detailed synthesis information of certain compounds provided below, one skilled in the art would immediately recognize the synthetic routes to the compounds of the present invention.
  • Crystal structures of p110 ⁇ have been reported, alone and in complex with ATP or pan-specific inhibitors such as LY294002 and wortmannin (Walker et al., 2000; Walker et al., 1999).
  • pan-specific inhibitors such as LY294002 and wortmannin
  • the crystal structures of PI3-K inhibitors from three chemotypes bound to human p110 ⁇ were determined at 2.5 - 2.6 A resolution: the quinazoline purine PIK-39, the imidazopyridine PIK-90 and the phenylthiazole PIK-93 ( Figure 2 ).
  • PIK-39 is an isoquinoline purine that inhibits p110 ⁇ at mid-nanomolar concentrations, p110 ⁇ and p110 ⁇ at concentrations ⁇ 100-fold higher, and shows no activity against any other PI3-K family member, including p110 ⁇ , at concentrations up to 100 ⁇ M ( Figure 5 ).
  • the biochemical selectivity of this compound is achieved through an unusual binding mode revealed in its co-crystal structure with p110 ⁇ ( Figure 2C ). Only the mercaptopurine moiety of PIK-39 makes contacts within the interior of the ATP binding pocket, and this ring system is rotated ⁇ 110° and twisted ⁇ 35° out of the plane relative to the adenine of the ATP. In this orientation, it satisfies hydrogen bonds to the backbone amides of Val 882 and Glu 880 (thereby recapitulating the hydrogen bonds made by N1 and N6 of adenine).
  • PIK-39 does not access the deeper pocket in the active site interior ( Figure 2C , lightly shaded area labeled as "Affinity Pocket”). Instead, the aryl-isoquinoline moiety of PIK-39 extends out to the entrance of the ATP binding pocket ( Figure 2B ). In this region, the kinase accommodates the inhibitor by undergoing a conformational rearrangement in which Met 804 shifts from an "up” position, in which it forms the ceiling of the ATP binding pocket, to a "down” position which it packs against the isoquinoline moiety.
  • PIK-90 and PIK-93 both make a hydrogen bond to the backbone amide nitrogen of Val 882 ( Figure 2D ), an interaction conserved among all known PI3-K inhibitors (Walker et al., 2000).
  • PIK-93 makes a second hydrogen bond to the backbone carbonyl of Val 882 and a third between its sulphonamide moiety and the side chain of Asp 964.
  • PIK-90 binds in a mode similar to PIK-93, although this larger compound makes more extensive hydrophobic interactions, burying 327 ⁇ 2 of solvent accessible surface area.
  • PIK-90 projects its pyridine ring into a deeper cavity that is partially accessed by PIK-93 but not occupied by ATP ( Figure 2D , lightly shaded circle).
  • Figure 2D lightly shaded circle
  • the pyridine ring of PIK-90 is poised to make a hydrogen bond to Lys 833, and we find that replacement of this pyridine nitrogen with carbon results in a 100-fold loss in affinity (PIK-95, Figure 4 ).
  • PI-103 a third multi-targeted PI3K inhibitor, projects a phenol into the same pocket based on an arylmorpholine pharmacophore model ( Figure 2D ).
  • PIK-39 does not exploit the PI3-kinase affinity pocket ( Figure 2C ).
  • PIK-294 novel analog containing an m-phenol
  • the structure of PIK-39 bound to p110 ⁇ reveals a conformational rearrangement of Met 804 that creates an induced pocket, and we have hypothesized that this conformational rearrangement underlies the selectivity of PIK-39 for p110 ⁇ .
  • a prediction of this model is that mutation of Met 804 should perturb the binding of p110 ⁇ -selective inhibitors (which access the induced pocket), but not affect other classes of inhibitors (which do not access this pocket).
  • Modeling suggests that mutation of Met 804 to a ⁇ -branched amino acid (such as valine or isoleucine) should restrict the pocket formed by rearrangement of that residue ( Figure 3B , right).
  • Antagonist modeling was performed using the PyMOL Molecular Graphics System. All p110 ⁇ crystal structures (PDB codes in parentheses), including the Apo (1E8Y), ATP (1E8X), Wortmannin (1E7U), LY294002 (1E7V), Quercetin (1E8W), Myricetin (1E90), and Staurosporine (1E8Z), PIK-90, PIK-93, and PIK-39 bound forms were structurally aligned using PyMOL's align function. Models for the inhibitors PIK-108, KU-55933, and PI-103 were built on top of the LY294002 arylmorpholine scaffold (1E7V) using PyMOL's fragment building function. A model for the inhibitor IC87114 was similarly built on top of the PIK-39 aryl-isoquinoline scaffold.
  • the model for PI-103 was built into the protein structure of p110 ⁇ bound to PIK-90, because the PIK-90 structure contains the enlarged affinity pocket that is necessary to accommodate PIK-103's phenolic moiety (the PIK-90 p110 ⁇ structure otherwise does not exhibit any conformational differences in the arymorpholine-binding region in comparison to the LY294002-bound p110 ⁇ structure).
  • the models for PIK-108, KU-55933, and IC87114 were built into the protein structure of p110 ⁇ bound to PIK-39 because these inhibitors possess bulky groups that project out of the adenine plane and are likely to exploit the unique "Met 804 down" induced-fit pocket.
  • the class I PI3-Ks were either purchased (p110 ⁇ /p85 ⁇ , p110 ⁇ /p85 ⁇ , p110 ⁇ /p85 ⁇ from Upstate, and p110 ⁇ from Sigma) or expressed as previously described (Knight et al., 2004). IC50 values were measured using either a standard TLC assay for lipid kinase activity (described below) or a high-throughput membrane capture assay. Kinase reactions were performed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 ⁇ g/ml).
  • TLC plates were then dried, exposed to a phosphorimager screen (Storm, Amersham), and quantitated.
  • kinase activity was measured at 10 - 12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (typically, 200 ⁇ M).
  • IC50 determinations were repeated two to four times, and the reported value is the average of these independent measurements.

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Claims (17)

  1. Composé choisi parmi les composés de formule suivante :
    Figure imgb0040
     dans laquelle :
    q est un entier de 0 à 5 ;
    z vaut 1 ;
    X est =N- ;
    L1 est une liaison ou un radical alkylène substitué ou non substitué, hétéroalkylène substitué ou non substitué, cycloalkylène substitué ou non substitué, hétérocycloalkylène substitué ou non substitué, arylène substitué ou non substitué, ou hétéroarylène substitué ou non substitué ; où le terme "alkylène" signifie un radical divalent dérivé d'un alkyle, et englobe le sous-ensemble "alcynylène" ;
    R1 et R2 sont indépendamment un halogène ou un radical -CN, -OR5, -S(O)nR6, -NR7R8, -C(O)R9, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué, où n est indépendamment un entier de 0 à 2 ;
    R3 est un radical alkyle en C1 à C4 non substitué ;
    R4 est un halogène ou un radical -OH, -CN, -NH2, alkyle, hétéroalkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, cycloalkyl-alkyle, hétérocycloalkyl-alkyle, arylalkyle, ou hétéroarylalkyle ;
    R5 est indépendamment l'hydrogène ou un radical -C(O)R10, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ;
    R6 est indépendamment l'hydrogène ou un radical -NR11R12, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué, où, si n vaut 1 ou 2, alors R6 est autre que l'hydrogène ;
    R7 est indépendamment l'hydrogène ou un radical alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ;
    R8 est indépendamment l'hydrogène ou un radical -S(O)nR13, -C(O)R14, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ;
    R9 est indépendamment l'hydrogène ou un radical -NR15R16, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ;
    R10 est indépendamment l'hydrogène ou un radical -NR17R18, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ;
    R14 est indépendamment l'hydrogène ou un radical -NR19R20, alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué ; et
    R11, R12, R13, R15, R16, R17, R18, R19 et R20 sont indépendamment l'hydrogène ou un radical alkyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, hétérocycloalkyle substitué ou non substitué, aryle substitué ou non substitué, ou hétéroaryle substitué ou non substitué.
  2. Composé selon la revendication 1, dans lequel R1 est un halogène ou un radical halogénoalkyle en C1 à C6 substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, aryl-alkyle en C1 à C6 substitué ou non substitué, ou hétéroaryl-alkyle en C1 à C6 substitué ou non substitué.
  3. Composé selon la revendication 2, dans lequel R1 est un radical phényle substitué ou non substitué, furanyle substitué ou non substitué, pyrrolyle substitué ou non substitué, thiophényle substitué ou non substitué, ou benzothiophényle substitué ou non substitué, indolyle substitué ou non substitué, quinolinyle substitué ou non substitué, pyridinyle substitué ou non substitué, 1H-pyrrolo[2,3-c]pyridinyle substitué ou non substitué, 1H-pyrrolo[2-3-b]pyridinyle substitué ou non substitué, thiazolyle substitué ou non substitué, imidazolyle substitué ou non substitué, oxazolyle substitué ou non substitué, isoxazolyle substitué ou non substitué, pyrazolyle substitué ou non substitué, isothiazolyle substitué ou non substitué, cyclohexyle substitué ou non substitué, morpholino substitué ou non substitué, pipéridinyle substitué ou non substitué, ou tétrahydropyridinyle substitué ou non substitué.
  4. Composé selon la revendication 1, dans lequel R1 est un radical phényle, furanyle, pyrrolyle, thiophényle ou benzothiophényle, chacun éventuellement substitué par un ou plusieurs substituants R21, où R21 est indépendamment
    (1) un halogène ou un radical -CN, -or, -C(O)R23, -NR24R25, -S(O)NR26R27, ou -S(O)wR28, où w est un entier de 0 à 2, et R22, R23, R24, R25, R26, R27 et R28 sont indépendamment l'hydrogène ou un radical alkyle, hétéroalkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, cycloalkyl-alkyle, hétérocycloalkyl-alkyle, arylalkyle, ou hétéroarylalkyle, éventuellement substitué par un radical alkyle non substitué, hétéroalkyle non substitué, cycloalkyle non substitué, hétérocycloalkyle non substitué, aryle non substitué, hétéroaryle non substitué, cycloalkyl-alkyle non substitué, hétérocycloalkyl-alkyle non substitué, arylalkyle non substitué, ou hétéroarylalkyle non substitué ; ou
    (2) un radical alkyle en C1 à C10, hétéroalkyle à 2 à 10 chaînons, cycloalkyle en C3 à C8, hétérocycloalkyle à 3 à 8 chaînons, ou aryle ou hétéroaryle éventuellement substitué par un halogène ou un radical -OH, -CN, -NH2, alkyle non substitué, hétéroalkyle non substitué, cycloalkyle non substitué, hétérocycloalkyle non substitué, aryle non substitué, hétéroaryle non substitué, cycloalkyl-alkyle non substitué, hétérocycloalkyl-alkyle non substitué, arylalkyle non substitué, ou hétéroarylalkyle non substitué.
  5. Composé selon la revendication 4, dans lequel R1 est un radical phényle substitué en positions méta et para, ou substitué en positions méta et méta.
  6. Composé selon la revendication 5, dans lequel R21 est un halogène ou un radical -OR22.
  7. Composé selon la revendication 6, dans lequel R21 est le fluor et R22 est l'hydrogène ou le radical méthyle.
  8. Composé selon l'une quelconque des revendications 1 à 7, dans lequel q vaut 1.
  9. Composé selon l'une quelconque des revendications 1 à 8, dans lequel R2 est un halogène ou un radical -OH, -CN, -NH2, alkyle non substitué, hétéroalkyle non substitué, cycloalkyle non substitué, hétérocycloalkyle non substitué, aryle non substitué, hétéroaryle non substitué, cycloalkylalkyle non substitué, hétérocycloalkyl-alkyle non substitué, arylalkyle non substitué ou hétéroarylalkyle non substitué, le fluor, ou un radical alkyle en C1 à C4 non substitué.
  10. Composé selon l'une quelconque des revendications 1 à 9, dans lequel L1 est un radical alkylène substitué ou non substitué ou alcynylène substitué ou non substitué.
  11. Composé selon l'une quelconque des revendications 1 à 10, dans lequel L1 est un radical méthylène substitué ou non substitué, éthylène substitué ou non substitué, propylène substitué ou non substitué, butylène substitué ou non substitué, éthynylène substitué ou non substitué, ou prop-2-ynylène substitué ou non substitué.
  12. Composé selon la revendication 11, dans lequel R1 est un radical -CN, -OR5, -NR7R8, cycloalkyle non substitué ou substitué par R21, aryle non substitué ou substitué par R21, hétéroaryle non substitué ou substitué par R21, alkyle en C1 à C4 non substitué ou substitué par R21, où
    R21 est un halogène ou un radical -OR22, -NR24R25, ou alkyle en C1 à C4 non substitué, et
    R5, R7, R8, R22, R24 et R25 sont indépendamment l'hydrogène ou un radical alkyle en C1 à C4 non substitué.
  13. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 12 et un excipient pharmaceutiquement acceptable.
  14. Composé selon l'une quelconque des revendications 1 à 12 pour utilisation dans une méthode de traitement du corps humain ou animal.
  15. Composé selon l'une quelconque des revendications 1 à 12 pour utilisation dans une méthode de traitement d'une malignité hématologique, d'une inflammation, d'une maladie auto-immune, d'une maladie cardiovasculaire, d'une leucémie myéloïde aiguë, d'une leucémie myéloïde chronique, d'une mastocytose, d'une leucémie lymphoblastique chronique, d'un myélome multiple, d'un syndrome myélodysplasique, d'une polyarthrite rhumatoïde, d'un lupus érythémateux disséminé, ou de l'asthme.
  16. Utilisation d'un composé selon l'une quelconque des revendications 1 à 12 dans la fabrication d'un médicament destiné au traitement d'une malignité hématologique, d'une inflammation, d'une maladie auto-immune, d'une maladie cardiovasculaire, d'une leucémie myéloïde aiguë, d'une leucémie myéloïde chronique, d'une mastocytose, d'une leucémie lymphoblastique chronique, d'un myélome multiple, d'un syndrome myélodysplasique, d'une polyarthrite rhumatoïde, d'un lupus érythémateux disséminé, ou de l'asthme.
  17. Utilisation d'un composé selon l'une quelconque des revendications 1 à 12 dans la fabrication d'un médicament destiné au traitement d'un lupus érythémateux disséminé.
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US20110301144A1 (en) 2011-12-08
EP2557080A1 (fr) 2013-02-13
CA2647391C (fr) 2015-12-29
JP2009532476A (ja) 2009-09-10
JP5597391B2 (ja) 2014-10-01
CA2909277A1 (fr) 2007-10-11
DK2004654T3 (da) 2013-07-22
EP2015752A4 (fr) 2010-03-31
WO2008127226A2 (fr) 2008-10-23
CA2647391A1 (fr) 2007-10-11
AU2007233302B2 (en) 2012-11-01
EP2004654A2 (fr) 2008-12-24
US20080032960A1 (en) 2008-02-07
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US20140288096A1 (en) 2014-09-25
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AU2007233302A1 (en) 2007-10-11
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US20070293516A1 (en) 2007-12-20
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US9493467B2 (en) 2016-11-15
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US20230111917A1 (en) 2023-04-13

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